Various kinds of substituted naphthalimides are known in the art as having anti-tumour effect or other useful biological activity.
Amonafide is an isoquinolinedione derivative which has undergone extensive tests for its anti-tumour activity. Although the level of activity found for amonafide was and continues to be of high interest, this material does have significant deficiencies which indicate the continuing need for agents with improved properties. In the first place, amonafide was found to be too toxic for some patients: in particular it has produced substantial myelotoxicity leading to some deaths in patients receiving five daily doses of the drug. In addition, it was shown that amonafide had only moderate activity in leukemia models in mice. Also, it was shown that amonafide has no activity in human tumour xenografts in mice with colon, lung and mammary cancers. Thus, while amonafide shows significant biological activity, it does not have a substantially broad spectrum of activity in murine tumour models. Ajani et al. in Invest New Drugs (1988) 6:79-83 has shown that amonafide has poor activity when tested in primary human solid tumours in vitro.
U.S. Pat. No. 5,635,506 discloses compounds based on anthracene instead of naphtalene and having the following formula:
wherein:                A is (CR4R5)n3, lower cycloalkylene or arylene or a chemical bond;        each R4 and R5 are independently hydrogen or lower alkyl;        D may be a chemical bond;        R12 and R13 may be independently hydrogen or an optionally substituted lower alkyl; and        n1, n2, R6, R7, R8, R9, R10 and R11 together form the substituting pattern of the anthracenyl moiety.        
These compounds are described as being useful in treating cancer in animals and humans, e.g. against malignant tumors (especially solid tumors and leukemia).
In particular, 2-[2′-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz(deh)isoquinoline-1,3-dione (also called “azonafide”) disclosed in this document showed anti-tumor activity on multidrug resistant tumors in vitro but did not completely maintain its activity with the human Myeloma 8226/DOX 40 cell line where a possible three-fold cross resistance was evident. Azonafide was also said to delay the appearance of tumors and to reduce tumor growth in mice with more efficiency than amonafide. On another hand, most of the compounds disclosed in this prior art document, including azonafide, showed a higher cardiotoxicity than amonafide.
Although the activity of antiproliferative agents such as amonafide or azonafide derivatives against certain forms of cancers can be shown, improvement in tumor response rates, duration of response, metastatic inhibition and ultimately patient survival are still sought. There is also a need in the art for improving the efficacy of antiproliferative treatments in humans by providing suitable combinations of new drugs with conventional antineoplastic agents. In view of the above-mentioned shortcomings of amonafide, azonafide and similar drugs available heretofore, the present inventors searched for azonafide derivatives which could demonstrate to be more effective anti-cancer agents. Specifically, they searched for compounds having one or more of the following characteristics:    1) increased tumor cell cytotoxic potency;    2) minimal, if any, cross resistance with multidrug resistant tumor cells;    3) relativity low cytotoxic potency in normal heart cells;    4) activity in a wide range of malignant tumors, especially solid tumors, hematological tumors, and leukemia; and    5) reduced myelotoxicity in humans at the tumor cell cytotoxic dosage.    6) Anti-migratory (anti-metastatic) effect
As a result of their research, the present inventors have developed the following compounds, methods and compositions meeting these objectives.